Stroke is the third leading cause of death in the United States (U.S.) and women account for 60% of all deaths from stroke. Major shifts in modifiable exposures over the past decade - increasing obesity and physical inactivity and decreasing menopausal hormone therapy (MHT) use - are changing the profile of women's health, but their effect on stroke among women is unclear. The California Teachers Study (CTS), a prospective cohort study that has actively followed 133,479 female California public school professionals for a broad range of health outcomes since 1995, is poised to evaluate how these societal transitions in modifiable exposures affect incidence of and mortality from stroke. The unique repository of life course exposure data on modifiable risk factors in the CTS cohort provides a near-singular resource for prospective assessment of women's health risks associated with long-term history of physical activity, longitudinal anthropometry data on body fat distribution, and detailed MHT use. Our specific aims address the impact of these shifting exposures both individually and together on stroke incidence and mortality, both overall and among the two major stroke subtypes (ischemic and hemorrhagic). In Aim 1, we will determine the impact of obesity and physical inactivity on the rates, risk, and population attributable fraction of incident and fatal stroke. Our detailed questionnaires permit us to evaluate the effect of lifelong and changing patterns of obesity phenotypes (defined as a combination of temporal changes in overall adiposity with adult body fat distribution) and physical activity, including by age and recency. In Aim 2, we will determine whether the effects on rates, risk and population attributable fraction observed from obesity and physical inactivity (Aim 1) become more pronounced in the years following widespread cessation of MHT use (after 2002). To accomplish these aims, we will calculate age-adjusted and age-specific annual incidence and mortality rates, standardized to the U.S. population in 2000. To calculate risk associations, we will use time-dependent exposure data on these key exposures from teenage years to old age and analyze associations with stroke risk and mortality using statistical approaches that account for missing data and secular changes in exposures. We will calculate the population attributable fraction for each etiologic risk factor, and by time period when MHT was widely used versus the recent sharp decline in use. Public Health Relevance: Successful completion of these aims will permit evaluation of the population impact of a decade of profound transition in obesity, physical activity, and MHT use on women's stroke incidence and mortality, and provide insight into the interplay between these and other relevant exposures. This proposal focuses on the etiology of stroke incidence and causes of stroke mortality and emphasizes common, modifiable, behavioral risk factors in ways that can facilitate future population-wide stroke prevention efforts. PUBLIC HEALTH RELEVANCE: The California Teachers Study spans more than a decade of profound transitions in women's health behaviors, including increasing physical inactivity and obesity, and decreasing use of hormone therapy. By examining how exposures to these common, modifiable risk factors over a woman's lifespan influences rates and risk of stroke incidence and mortality, this study will provide critical new knowledge that can serve as the basis for behavioral public health interventions that benefit women on a population-wide scale.